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G. L. King, C. Li, J. Hiraoka-Yamamoto, A. Clermont; Endothelial Specific Overexpression of Protein Kinase C β2 (PKC) Mimics Vascular Dysfunctions in Diabetic Retinopathy (DR). Invest. Ophthalmol. Vis. Sci. 2010;51(13):5636.
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© ARVO (1962-2015); The Authors (2016-present)
The role of endothelial dysfunction (ED) without pericyte apoptosis in the development of DR is unknown. PKCβ activation in the vascular tissues is linked to DR and systemic ED. To define the effect of PKCβ activation on retinal endothelium in the development of DR, transgenic mice overexpressing PKCβ2 targeted to endothelial cells using VE-cadherin promoter (ECPKCβ2Tg), were created and studied.
Retinal vascular function was studied in wildtype (WT) and ECPKCβ2Tg C57/B6 mice by measuring mean circulation time (MCT) and retinal blood flow (RBF) by dye-dilution method, and capillary permeability via perfusion with Evans blue dye. All mRNA expressions were quantified by real-time PCR. Retinal angiogenic responses to ischemia were assessed by retinopathy of prematurity (ROP) models.
Systemic characteristics exhibited by WT and ECPKCβ2 mice were comparable with respect to body weight, plasma glucose and lipid levels, and insulin sensitivity. The expression of PKCβ2 mRNA and protein levels and total PKC activity in ECPKCβ2Tg mice increased by 2-3 fold (p<0.5), respectively, in retinal microvessels vs. WT mice. RBF significantly decreased in parallel with increased endothelin 1 (ET-1) mRNA expression in the retina, mimicking retinal changes in diabetic rodents and patients. Capillary permeability in the retina was also elevated (47%) in parallel with increased VEGF mRNA expression (39%) in ECPKCβ2Tg mice compared to WT (p<0.05). Exposure of neonatal mice to hyperoxia in ROP condition showed that ECPKCβ2Tg mice exhibited significant greater central avascular area, number of vascular tufts and clusters in retinal flat mounts (by fluorescence dextrans) and pre-retinal neovascular nuclei (p<0.05) compared to WT. The increases in retinal angiogenic responses paralleled elevations of VEGF and ET-1 mRNA levels but not eNOS mRNA levels in the retina of ECPKCβ2Tg vs. WT mice.
Activation of PKCβ2 in endothelium of retina can cause increases in retinal permeability and angiogenesis, and a decrease in RBF, mimicking vascular changes in DR. Thus ED alone can induce DR, without pericyte abnormalities or apoptosis.
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